Summary Alpha adrenergic receptor blockers (?-blockers) are a first line therapy for relaxing muscle tension to improve voiding in patients with lower urinary tract symptoms (LUTS), but are most effective on smaller, non-fibrotic prostates. Steroid 5a-reductase inhibitors (5ARI) block the local production of dihydrotestosterone (DHT), representing the only therapy for shrinking prostate volume through apoptosis of luminal epithelia. Combining both of these therapies is expensive, has unwanted side effects, and fails to fully slow the risk of symptomatic progression. These data suggest that we have yet to target the variety of pathogeneses regulating BPH progression. Understanding the molecular pathogenesis of 5ARI resistance is a High-Priority Recommendation of the NIDDK Strategic Plan for Prostate Research. The potential links between variable drug response and histopathological features are poorly studied. We present an innovative approach to deconstructing the molecular pathogenesis of a prevalent 5ARI resistant phenotype: the glandular nodule. The conflicting data on the pathogenesis of BPH is largely due to a lack of comprehensive translational human tissue studies that account for heterogeneity by binning specimens into histopathological categories. We focus here on a glandular nodule phenotype observable in ~60% of our patients and demonstrate two key points in our preliminary data: 1) LC-MS/MS of androgen and 5ARI levels in patients revealed that 5ARIs are functioning to reduce DHT in nodules, but are failing to induce luminal epithelial apoptosis, suggesting 5ARI resistance; and 2) RNA-seq of luminal epithelia from 5ARI resistant nodules shows elevated Notch pathway activity. We will test the hypothesis that luminal epithelial Notch signaling drives 5ARI-resistant nodule formation in human BPH with three critical pieces of evidence: 1) MRI will be sequentially performed on patients before and after 5ARI treatment to identify whether glandular nodules regress; 2) nodular surgical specimens from 5ARI-resistant patients will be examined by LC-MS/MS and histopathology for correlating DHT independence with Notch activity; and 3) glandular nodule explants and transgenic animals with ectopic Notch activation will be treated to determine whether Notch inhibition sensitizes the prostate to 5ARI treatment. Successful completion of our aims will establish a molecular and phenotypic classification of 5ARI-resistance and a clinical tool for non-invasive discrimination of patients with 5ARI-resistant glandular nodules. Relevance New insight into how BPH patients fail 5ARI therapy holds great promise for identifying novel approaches to medical therapy in the treatment of BPH.